PROJECT SUMMARY Age is the strongest risk factor for brain diseases related to accumulation of misfolded proteins and also the risk for vascular diseases. So far, there is little evidence that excessive production of proteins forming brain deposits in neurodegenerative conditions contributes to their pathology. A reduced clearance of brain waste has emerged as a possible factor underlying disease development. Cerebral blood flow (CBF) and vascular pulsations facilitate the passage of extracellular fluid through the brain, a channel for removing waste products. We contend that both CBF and brain clearance depend on proper structure and health of brain vessels. Indeed vascular conditions are significant risk factors for neurodegeneration. Although epidemiological studies point out to vascular disease as a major risk factor for dementia, and corroborate related CBF reductions, there is no direct evidence in humans supporting the pathway: vascular disease ? hemodynamic impairment ? clearance deficit ? neurodegeneration We propose to examine this pathway, using our newly developed Positron Emission Tomography (PET)-based tool to estimate brain clearance. Over 5 years we will conduct a 24-month longitudinal study of 70 cognitively healthy subjects 60-80 years old, classified at baseline into: 1) normotensive NT (n=20), 2) controlled hypertension C-HTN (n=20), 3) Uncontrolled hypertension or Untreated hypertension UU-HTN (n=30). Our goals are: AIM1. To test the relationship between vascular disease (HTN), reduced CBF and impaired brain clearance AIM2. To examine whether treatment of HTN restores CBF and improves brain clearance AIM3. To tests whether HTN, CBF and brain clearance predict markers of neurodegeneration and cognitive performance and whether clearance mediates the effects of HTN and CBF on these markers. We chose HTN since it is a common risk factor for neurodegenerative diseases. Our preliminary work documented its association with hemodynamic deficits, and showed that with longitudinal reduction in blood pressure these deficits may be reversible. As an index of neurodegeneration we will use cerebrospinal fluid t- tau/a?42 ratio (total tau/ amyloid?-42) ? a biomarker of Alzheimer's disease (AD). AD is by far the most common age-related neurodegenerative disease and we have reported that higher vascular burden is related to more abnormal AD biomarkers. This project will advance our understanding of how common vascular condition affects the brain and facilitates neurodegeneration. Advanced imaging and analytical techniques implemented by an experienced team with a long record of collaboration, permit a comprehensive and novel approach to essential questions.